Synthesis of bioactive 2-(2-(difluoromethoxy)aryl)benzo[d]thiazole derivatives via base-promoted one-pot process

Article abstract of DOI:10.1016/j.tet.2019.130472

A convenient synthesis of 2-(2-(difluoromethoxy)aryl)benzo[d]thiazoles from 2- (o-hydroxyaryl)benzothiazoles and commercially available ethyl difluoroiodoacetate (ICF₂CO₂Et) is described. The transformation was amenable to a one-pot,

Full text of DOI:10.1016/j.tet.2019.130472

Accepted Manuscript
Synthesis of bioactive 2-(2-(difluoromethoxy)aryl)benzo[d]thiazole derivatives via
base-promoted one-pot process
Huiping Zeng, Puying Luo, Manling Luo, Hao Ding, Qiuping Ding
PII:
S0040-4020(19)30786-0
DOI:
https://doi.org/10.1016/j.tet.2019.130472
Article Number: 130472
Reference:
TET 130472
To appear in: Tetrahedron
Received Date: 19 May 2019
Revised Date: 12 July 2019
Accepted Date: 22 July 2019
Please cite this article as: Zeng H, Luo P, Luo M, Ding H, Ding Q, Synthesis of bioactive 2-(2-
(difluoromethoxy)aryl)benzo[d]thiazole derivatives via base-promoted one-pot process, Tetrahedron
(2019), doi: https://doi.org/10.1016/j.tet.2019.130472.
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ACCEPTED MANUSCRIPT
Synthesis of bioactive 2-(2-(difluoromethoxy)aryl)benzo[d]thiazole
derivatives via base-promoted one-pot process
ꢀ
Huiping Zeng,a Puying Luo,* b Manling Luo,b Hao Ding,a and Qiuping Ding,*, a
aKey Laboratory of Small Functional Organic Molecule, Ministry of Education and
Jiangxi's Key Laboratory of Green Chemistry, Jiangxi Normal University, Nanchang,
Jiangxi 330022, P.R. of China.
bDepartment of Obstetrics and Gynecology, Jiangxi Provincial people’s Hospital,
Nanchang, Jiangxi 330006, P. R. China.
Abstractꢁ
A convenient synthesis of 2-(2-(difluoromethoxy)aryl)benzo[d]thiazoles from 2-
(o-hydroxyaryl)benzothiazoles and commercially available ethyl difluoroiodoacetate
(ICF2CO2Et) is described. The transformation was amenable to a one-pot, sequential
three-component protocol from o-hydroxybenzaldehyde, o-aminothiophenol, and
ICF2CO2Et promoted by KOH. Additionally, some of the prepared compounds
exhibited promising activity against human ovarian cancer cells.
Keywords: 2-arylbenzo[d]thiazoles; O-difluoromethylation; o-hydroxybenzaldehyde;
o-aminothiophenol; ethyl difluoroiodoacetate.
The introduction of fluorine atom or fluorinated groups into active organic molecules
can distinctly modulate their membrane permeability, metabolic stability, and
* Corresponding author
ꢁTel.: +86 791 88130095; fax: +86 791 88120388; E-mail: dqpjxnu@gmail.com (Q. Ding).
Tel.:+86 791 86897371; E-mail: luopuying1979@126.com (P. Luo)
1

ACCEPTED MANUSCRIPT
bioavailability.1 Therefore, organofluorine compounds have been widely employed in
pharmaceuticals, agrochemicals, and biological molecules.2 Among these fluorinated
molecules, difluoromethyl ethers have attracted great interest as candidates for
modern drug discovery.3 A wide range of OCF2H-containing organic molecules
exhibit anti-inflammary, anti-tumour, anti-bacterial, and antimicrobial activity (Figure
1).4-7 For instance, Roflumilast is a commercially available drug used in COPD
patients.4,5 Pantoprazole is also a widely used anti-ulcer pharmaceutical agent.4
Fluoromycin is a fluorescent-labeled derivative of talisomycin S10b, and can be used
as a fungicide.6 Pyroxasulfone was found to be a novel herbicide for soybean, wheat
and corn.7 Consequently, the development of efficient methods for the synthesis of
OCF2H-containing organic molecules from commercially available substrates is
highly desired.
2-Arylbenzothiazoles have attracted great attention because such kinds of
heterocycles exhibit an extensive range of biological activities, such as antitumor,
antiviral, and antimicrobial properties.8,9 For instance, fluorine-containing compound
I was discovered to be a potent S1P1 agonist (EC50 = 0.017 ꢀM),8 while compound II
could suppress the growth of trypanosomes (Figure 2).9 As part of our interest in C-H
functionalization of 2-arylbenzothiazoles,10 herein we wish to describe a simple and
convenient
approach
for
the
synthesis
of
2-(2-(difluoromethoxy)aryl)benzo[d]thiazoles and examine their bioactivities.
2

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Figure 1. Examples of bioactive compounds possessing an OCF2H group.
Figure 2. F-containing 2-arylbenzothiazole-based bioactive molecules.
Recently, much attention has focused on the development of efficient approaches
for the synthesis of difluoromethyl ethers via the base-promoted
O-difluoromethylation of phenols,11 alcohols,12 and ketones13 using various precursors
of difluorocarbene. A variety of difluoromethylating agents have also been employed
successfully.11-13 For example, Hartwig and Fier developed a difluoromethylation of
phenols with HCF2OTf in the presence of KOH.11f Shen and co-workers described the
direct difluoromethylation of alcohols using an electrophilic difluoromethylated
sulfonium ylide.12b Shibata and co-workers reported the organic base-promoted direct
O-difluoromethylation of 1,3-diones via the in situ generation of difluorocarbene from
bromodifluoromethylating reagents.13d However, a number of these fluoromethylating
agents (HCF2Cl, HCF3, and CHF2I) are gases, which are difficult to handle. In
addition, some of them are low reactivity or difficult to prepare. Therefore, the new,
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simple and efficient reagents for the difluoromethylation of alcohols and phenols are
also greatly desired.
Table 1 Optimization of reaction conditionsa.
Entry
1
2
3
4
5
6
7
8
Base
K2CO3
K2CO3
K2CO3
KOH
Na2CO3
KF
X (2)
Cl (2a)
Br (2b)
I (2c)
I (2c)
I (2c)
I (2c)
I (2c)
I (2c)
I (2c)
I (2c)
I (2c)
I (2c)
I (2c)
I (2c)
I (2c)
y (equiv)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
-
Yield (%)d
trace
20
40
51
trace
trace
40
trace
60
65
68
72
82
Cs2CO3
-
9
KOH
KOH
KOH
KOH
KOH
KOH
KOH
3.0
5.0
6.0
7.0
6.0
7.0
6.0
10
11
12
13b
14b
15c
83
61
aReaction conditions: 1a (0.2 mmol), 2 (0.24 mmol, 1.2 equiv), base (x equiv),
CH3CN (2 mL), rt, 12 h. bIn the presence of 2.0 equiv of 2. cAt 50 oC. dYield based on
1a.
Based on previous work,11b the reaction of 2-(2-hydroxyphenyl)benzothiazole 1a
and ethyl chlorodifluoroacetate 2a (1.2 equiv) was initially chosen as a template to
optimize the reaction conditions (Table 1, entry 1). Regretfully, only trace of desired
product was observed. Fortunately, when ethyl 2-bromo-2,2-difluoroacetate 2b and
ethyl 2,2-difluoro-2-iodoacetate 2c were used as difluoromethylating agents in the
presence of potassium carbonate (1.0 equiv) in acetonitrile at room temperature, the
desired o-difluoromethoxylated product 3a was obtained in 20% and 40% yield,
respectively (Table 1, entries 2 and 3). Regrettably, the screening of different solvents
4

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showed that almost no reaction occurred in toluene, dimethyl sulfoxide, glacial acetic
acid, methanol, 1,4-dioxane, DMF, and DMAc. Next, the screening of bases revealed
that potassium hydroxide was better than others (Table 1, entries 4-7). Trace amounts
of the desired product were observed in the absence of base (Table 1, entry 8).
Increasing the amount of KOH from 1.0 to 7.0 equivalents gave higher yields of the
desired product; the yield increased to 72% when 7.0 equivalent of KOH was used
(Table 1, entry 12). Further studies showed that the yield of 3a could be increased to
82% when 2.0 equivalents of 2c were employed (Table 1, entry 13). When the
reaction temperature was increased to 50 oC, the desired product was obtained in only
61% yield, showing that reaction temperature has a significant impact on product
yield (Table 1, entry 15).
With the optimized reaction conditions in hand (Table 1, entry 13), we explored the
substrate scope of the 2-(2-hydroxyaryl)benzothiazoles 1 (Table 2). The results show
that the methodology can be applied to a broad range of substrates. Substrates bearing
electron-withdrawing or electron-donating groups underwent reaction smoothly. The
reaction was compatible with various substituents, such as methoxy, N,N-diethyl,
methyl, fluoro, chloro, bromo, and nitro groups. In comparison, substrates bearing
electron-donating groups gave their corresponding products in moderate yields,
whereas substrates bearing electron-withdrawing groups gave the desired products
with good to excellent yields. For instance, the reaction of N,N-diethyl substituted
substrate 1c with ethyl difluoroiodoacetate 2c gave the corresponding product 3c in
only 40% yield. However, the nitro substituted 2-(2-hydroxyphenyl)benzothiazole 1k
5

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reacted smoothly with 2c to give the corresponding target product 3k in 97% yield.
Similarly, the analogue 1-(benzo[d]thiazol-2-yl)naphthalen-2-ol 1o gave the
corresponding difluoromethoxylated product 3o in 70% yield.
Table 2 Substrate scope for difluoromethylation of 2-(2-hydroxyaryl)benzothiazoles
1a
ICF2COOEt
2c (2.0 equiv)
HO
HF2CO
S
S
R1
R1
R2
R2
KOH (6.0 equiv)
CH3CN, rt., 12 h
N
N
1
3
HF2CO
S
HF2CO
S
HF2CO
S
C2H5
N
C2H5
OMe
CH3
N
N
N
3b, 77%
3c, 40%
3d, 52%
HF2CO
S
HF2CO
S
HF2CO
S
F
N
N
N
CH3
OMe
3e, 66%
3f, 53%
3g, 55%
HF2CO
S
HF2CO
S
HF2CO
S
N
N
N
Br
Cl
F
3h, 86%
3i, 72%
3j, 85%
HF2CO
S
HF2CO
S
HF2CO
S
N
N
N
F
NO2
Br
3k, 97%
3l, 55%
3m, 77%
HF2CO
S
HF2CO
S
HF2CO
S
Br
Br
N
N
N
Cl
3n, 60%
3o, 70%
3p, 81%
HF2CO
S
Br
Cl
HF2CO
S
HF2CO
S
MeO
Cl
N
N
N
3q, 81%
3r, 50%
3s, 84%
HF2CO
S
HF2CO
S
HF2CO
S
Cl
Cl
Cl
N
N
N
NO2
OMe
Br
3t, 60%
3u, 70%
3v, 87%
6

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aReaction conditions: 1 (0.2 mmol), 2c (0.24 mmol, 1.2 equiv), KOH (6.0 equiv),
CH3CN (2 mL), rt, 12 h.
It is well-known that 2-(o-hydroxyphenyl)benzothiazoles can be easily prepared via
the
cyclocondensation/oxidation
5a.
of
o-amino
thiophenol
envisaged
4a
that
and
a
o-hydroxybenzaldehyde
Therefore,
we
cyclocondensation/oxidation and a subsequent difluoromethyl etherification could be
conducted in one-pot. Thus, we performed a three-component reaction of
o-hydroxybenzaldehyde 5a, o-aminothiophenol 4a (1.2 equiv), and ICF2COOEt 2c
(2.0 equiv) in EtOH/acetonitrile in the presence of KOH (6.0 equiv). The in situ
formed 2-(o-hydroxyphenyl)benzothiazole was converted to the difluoromethyl ether
product 3a in 75% yield. A range of o-amino thiophenols 4 and
o-hydroxybenzaldehydes 5 were amenable to the cascade reaction conditions, giving
the corresponding products 3 in good yields (Table 3).
Table 3 One-pot three-component reactiona
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aReaction conditions: (1) 5 (0.2 mmol), 4 (0.24 mmol, 1.2 equiv), KOH (6.0 equiv),
o
EtOH (2 mL), 80 C, 12 h. (2) 2c (0.4 mmol, 2 equiv), KOH (6.0 equiv), CH3CN (2
mL), rt, 12 h.
According to previous reports,11-13 a plausible mechanism of this cascade reaction
has been proposed, as shown in Scheme 1. First, the cyclocondensation/oxidation of
o-amino thiophenol 4 and o-hydroxybenzaldehyde 5 under an air atmosphere affords
2-(o-hydroxyphenyl)benzothiazole 1. Subsequently, the transformation may involve
the traditional catalytic model via generation of a difluorocarbene intermediate, which
is formed in situ from ethyl difluoroiodoacetate 2c in the presence of KOH. The
difluorocarbene is attacked by a phenoxide (ArO-) species to give the intermediate 7
-
(ArOCF2 ), which is then converted to the target product 3 in the presence of water
8

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(Path a). Alternatively, 1 undergoes an intermolecular nucleophilic substitution
reaction with ethyl difluoroiodoacetate 2c upon treatment with KOH, yielding ethyl
2-(2-(benzo[d]thiazol-2-yl)phenoxy)-2,2-difluoroacetate
8.
Next,
the
2-(2-(benzo[d]thiazol-2-yl)phenoxy)-2,2-difluoroacetic acid anion 9 is generated via
the alkaline hydrolysis of compound 8 using KOH as a base. Finally, the
decarboxylation of 9 produces the desired product 3 (Path b).14 Compounds 8 and 9
haven’t been isolated in our reaction system, although they were observed by LC-MS.
Scheme 1 Possible mechanism for the difluoromethoxylation
.
To evaluate the bioactivities of the 2-(2-(difluoromethoxy)aryl)benzo[d]thiazoles, a
general screening of their antitumor activities was performed using an MTT assay.
Preliminary results showed that some of the compounds exhibited good activity
against human ovarian cancer cells (SKOV3). For example, compound 3l, bearing a
bromo group at the ortho- position of the 2-phenyl ring, displayed promising activity
(IC50 = 92.0 ꢀM, 48 h) against human ovarian cancer cells (SKOV3), comparing
9

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favourably with cisplatin (IC50 =135.2 ꢀM, 48 h).15
Conclusion
In summary, we have developed a simple and efficient method for the synthesis of
2-(2-(difluoromethoxy)aryl)benzo[d]thiazoles
via
the
reaction
of
2-(o-hydroxyaryl)benzothiazoles with commercially available and easily handled
ethyl difluoroiodoacetate (ICF2COOEt). In addition, the methodology was
successfully employed in
a
one-pot, three-component process involving
o-hydroxybenzaldehyde, o-aminothiophenol, and ICF2COOEt in the presence of KOH.
Furthermore, some of the target compounds exhibited good anti-ovarian cancer cell
activity.
EXPERIMENTAL SECTION
Nuclear magnetic resonance (NMR) spectra are recorded in parts per million from
19
internal tetramethylsilane on the δ scale. 1H, 13C and F NMR spectra were recorded
on a Bruker AV-400 spectrometer operating at 400 MHz, 100 MHz and 376 MHz
respectively. All chemical shift values are quoted in ppm and coupling constants
quoted in Hz. High resolution mass spectrometry (HRMS) spectra were obtained on a
micrOTOF II instrument.
General Procedure for difluoromethylation of of 2-(2-hydroxyaryl)benzothiazoles 3.
2-(o-Hydroxyphenyl)benzothiazoles were synthesized according to the reported
procedures.16
2-(o-Hydroxyaryl)benzo[d]thiazole 1 (0.2 mmol), potassium hydroxide (6 equiv,
10

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67.3 mg), acetonitrile (2 mL) and ethyl difluoroiodoacetate 2 (2.0 equiv, 100 mg)
were continuously added to a 20 mL reaction tube. The reaction was stirred at 25 oC
for 12 h. After completion of the reaction, it was detected by a TLC thin-layer silica
gel plate, evaporation of the solvent under reduced pressure followed purification by
silica gel chromatography using petroleum ether: ethyl acetate = 50:1 as eluent to give
2-(o-difluoromethoxyphenyl) benzo[d]thiazole 3.
Experimental data for compounds 3
2-(2-(Difluoromethoxy)phenyl)benzo[d]thiazole (3a). Colorless solid, 45.5 mg
o
1
(82%), mp 51-53 C. H NMR (400 MHz, CDCl3) δ 8.48 (dd, J =1.6, 7.6 Hz, 1H),
8.11 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.53 – 7.46 (m, 2H), 7.43 – 7.36 (m,
2H), 7.29 (d, J = 8.4 Hz, 1H), 6.69 (t, J = 73.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 161.9, 152.4, 148.8, 136.1, 131.6, 130.6, 126.2, 125.9, 125.7, 125.3, 123.3, 121.4,
1
119.6, 116.1 (t, JC-F = 260 Hz).19F NMR (376 MHz, CDCl3) δ -80.42. HRMS (ESI):
m/z [M + H]+ calcd for C14H10F2NOS+: 278.0446; found: 278.0450.
2-(2-(Difluoromethoxy)-4-methoxyphenyl)benzo[d]thiazole (3b). Colorless solid,
1
47.5 mg (77%), mp 102-104 oC. H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.8 Hz,
1H), 8.04 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.35
(t, J = 7.6 Hz, 1H), 6.86 (dd, J = 8.8, 2.4 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.66 (d, J
= 73.2 Hz, 1H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.3, 162.0, 152.4,
149.9 (t, JC-F = 3.0 Hz), 135.6, 131.6, 126.1, 124.9, 122.9, 121.3, 118.3, 116.1 (t, 1JC-F
19
= 260 Hz), 111.4, 105.6, 55.7. F NMR (376 MHz, CDCl3) δ -80.50. HRMS (ESI):
m/z [M + H]+ calcd for C15H12F2NO2S+: 308.0551; found: 308.0556.
11

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4-(Benzo[d]thiazol-2-yl)-3-(difluoromethoxy)-N,N-diethylaniline (3c). Yellow solid,
1
28 mg (40%), mp 69-71 oC. H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.8 Hz, 1H),
8.01 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.32 (t, J =
7.6 Hz, 1H), 6.64 (t, J = 74.0 Hz, 1H), 6.62 (dd, J = 9.6, 2.8 Hz, 1H), 6.44 (d, J = 2.4
Hz, 1H), 3.42 (q, J = 7.2 Hz, 4H), 1.22 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 163.1, 152.7, 150.7, 150.4, 135.4, 131.4, 125.9, 124.2, 122.3, 121.2, 116.5 (t,
1JC-F = 259 Hz), 112.5, 109.0, 101.9, 44.7, 12.5. 19F NMR (376 MHz, CDCl3) δ -79.62.
HRMS (ESI): m/z [M + H]+ calcd for C18H18F2N2OS+: 349.1181; found: 349.1188.
2-(2-(Difluoromethoxy)-4-methylphenyl)benzo[d]thiazole (3d). Colorless solid,
1
30.3 mg (52%) , mp 129-131 oC . H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.0 Hz,
1H), 8.08 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.39
(t, J = 7.2 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 6.67 (t, J = 73.2 Hz, 1H),
2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.1, 152.4, 148.8, 142.8, 135.9, 130.3,
1
126.8, 126.2, 125.1, 123.1, 122.9, 121.4, 120.1, 116.2 (t, JC-F = 260 Hz), 21.5. 19F
NMR (376 MHz, CDCl3) δ -80.21. HRMS (ESI): m/z [M+H]+ calcd for
C15H12F2NOS+: 293.0602; found: 293.0648.
2-(2-(Difluoromethoxy)-4-fluorophenyl)benzo[d]thiazole (3e). Yellow solid, 39 mg
1
(66%), mp 82-84 oC. H NMR (400 MHz, CDCl3) δ 8.51-8.47 (m, 1H), 8.08 (d, J =
8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 6.8 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H),
7.08 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 6.68 (t, J = 72.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 163.9 (d, JC-F = 253 Hz), 161.0, 152.3, 149.4 (d, JC-F = 11 Hz),
135.7, 132.1 (d, JC-F = 10 Hz), 126.3, 125.3, 123.2, 122.0, 121.4, 115.8 (t, JC-F = 262
12

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19
Hz), 113.2 (d, JC-F = 21 Hz), 107.5 (d, JC-F = 25 Hz). F NMR (376 MHz, CDCl3) δ
-81.25, -106.06. HRMS (ESI): m/z [M+H]+ calcd for C14H9F3NOS +: 296.0351; found:
296.0357.
2-(2-(Difluoromethoxy)-5-methoxyphenyl)benzo[d]thiazole (3f). Colorless solid,
o
1
32.6 mg (53.2%), mp 85-87 C. H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz,
1H), 7.97 (d, J = 3.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.40
(t, J = 7.6 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.00 (dd, J = 9.2, 3.2 Hz, 1H), 6.59 (t, J =
73.6 Hz, 1H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 157.3, 152.3, 142.4,
136.1, 126.8, 126.3, 125.4, 123.3, 121.9, 121.4, 118.2, 116.4 (t, J = 261 Hz), 55.9. 19F
NMR (376 MHz, CDCl3) δ -80.32. HRMS (ESI): m/z [M+H]+ calcd for
C15H12F2NO2S+: 308.0551; found: 308.0564.
2-(2-(Difluoromethoxy)-5-methylphenyl)benzo[d]thiazole (3g). Colorless solid, 32
mg (55%) mp 70-72 oC. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 2.0 Hz, 1H), 8.11
(d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.51 (dt, J = 1.2, 7.6 Hz, 1H), 7.41 (t, J =
7.6 Hz, 1H), 7.28 (dd, J = 2.0, 8.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.64 (t, J = 73.6
Hz, 1H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.2, 152.4, 146.7, 136.0,
135.9, 132.3, 130.6, 126.2, 125.3, 125.2, 123.2, 121.4, 119.8, 116.3 (t, 1JC-F = 260 Hz),
20.7. 19F NMR (376 MHz, CDCl3) δ -80.35. HRMS (ESI): m/z [M+H]+ calcd for
C15H12F2NOS+: 296.0602; found: 296.0596.
2-(5-Bromo-2-(difluoromethoxy)phenyl)benzo[d]thiazole (3h). Yellow solid, 61.3
o
1
mg (86%), mp 103-105 C. H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 2.4 Hz, 1H),
8.10 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.57 – 7.50 (m, 2H), 7.42 (t, J = 7.6
13

ACCEPTED MANUSCRIPT
Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.66 (t, J = 72.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 160.2, 152.2, 147.6, 136.1, 134.2, 133.0, 127.4, 126.5, 125.7, 123.5, 121.4,
1
19
121.3, 119.2, 115.8 (t, JC-F = 262 Hz), 29.7; F NMR (376 MHz, CDCl3) δ -80.76.
HRMS (ESI): m/z [M + H]+ calcd for C14H9BrF2NOS +: 355.9551; found: 355.9560.
2-(5-Chloro-2-(difluoromethoxy)phenyl)benzo[d]thiazole (3i). Colorless solid, 44.9
mg (72%), mp 84-86 oC. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 2.4 Hz, 1H), 8.11
(d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.44 – 7.40 (m,
2H), 7.24 (d, J = 8.8 Hz, 1H), 6.66 (t, J = 72.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 160.3, 152.2, 147.0, 136.1, 131.7, 131.3, 130.1, 127.1, 126.5, 125.7, 123.5, 121.4,
121.2, 115.9 (t, 1JC-F = 262 Hz); 19F NMR (376 MHz, CDCl3) δ -80.80. HRMS (ESI) :
m/z [M + H]+ calcd for C14H9ClF2NOS+: 312.0056; found: 312.0066.
2-(2-(Difluoromethoxy)-5-fluorophenyl)benzo[d]thiazole (3j). Colorless solid, 50.2
1
mg (85%), mp 99-101 oC. H NMR (400 MHz, CDCl3) δ 8.21 (dd, J = 9.2, 3.2 Hz,
1H), 8.10 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.52 (dt, J = 1.2, 7.6 Hz, 1H),
7.42 (d, J = 7.6 Hz, 1H), 7.28 (dd, J = 9.2, 4.4 Hz, 1H), 7.19-7.14 (m, 1H), 6.64 (t, J =
72.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.5 (d, 4JC-F = 2.4 Hz), 160.0 (d, 1JC-F
4
4
= 244 Hz), 152.2, 144.5 (d, JC-F = 2.7 Hz), 136.1, 127.7 (d, JC-F = 8.0 Hz), 126.5,
125.7, 123.5, 121.9 (d, 4J = 8.5 Hz), 121.5, 118.2 (d, 2JC-F = 24 Hz), 116.7 (d, 2JC-F
=
1
19
25.6 Hz), 116.1 (t, JC-F = 261 Hz); F NMR (376 MHz, CDCl3) δ -80.69, -115.50.
HRMS (ESI): m/z [M + H]+ calcd for C14H9F3NOS +: 296.0351; found: 296.0361.
2-(2-(Difluoromethoxy)-5-nitrophenyl)benzo[d]thiazole (3k). Red solid, 62.5 mg
(97%), mp 169-170 oC. 1H NMR (400 MHz, CDCl3) δ 9.45 (d, J = 3.2 Hz, 1H), 8.34
14

ACCEPTED MANUSCRIPT
(dd, J = 2.8, 9.2 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.57 (dt, J
= 1.2, 9.2 Hz,1H), 7.47 (dt, J = 0.8, 8.0 Hz,1H), 7.45 (d, J = 9.2 Hz,1H), 6.84 (t, J =
71.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.0, 152.3, 152.1, 145.1, 136.1, 126.8,
1
19
126.4, 126.2, 126.0, 123.8, 121.5, 119.2, 115.3 (t, JC-F = 265.8 Hz). F NMR (376
+
MHz, CDCl3) δ -81.73. HRMS (ESI): m/z [M+H]+ calcd for C14H8F2N2O3S :
323.0296; found: 323.0298.
2-(2-Bromo-6-(difluoromethoxy)phenyl)benzo[d]thiazole (3l). Colorless oil, 39 mg
1
(55%). H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz,
1H), 7.58 (dd, J = 1.2, 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H),
7.36 (t, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.48 (t, J = 73.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 161.7, 152.9, 150.2, 136.4, 132.0, 130.2, 128.5, 126.3, 125.8,
1
124.8, 123.9, 121.6, 119.2, 115.9 (t, JC-F = 261 Hz), 29.71.19F NMR (376 MHz,
CDCl3) δ -81.46. HRMS (ESI): m/z [M+H]+ calcd for C14H9BrF2NOS+: 355.9551;
found: 355.9554.
2-(2-(Difluoromethoxy)-6-fluorophenyl)benzo[d]thiazole (3m). Yellow oil, 34 mg
1
(58%). H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz,
1H), 7.52 (dt, J = 1.2, 8.0 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.15-7.10 (m, 2H), 6.62 (t, J
1
= 73.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.8 (d, JC-F = 253 Hz), 156.7,
3
153.0, 149.7, 136.1, 131.8 (d, JC-F = 10 Hz), 126.2, 125.7, 123.8, 121.4, 116.4 (d,
2
1
2
4JC-F = 3 Hz), 116.2 (t, JC-F = 15 Hz), 116.1 (t, JC-F = 261 Hz), 113.6 (d, JC-F = 22
Hz); 19F NMR (376 MHz, CDCl3) δ -81.90, -109.49. HRMS (ESI): m/z [M+H]+ calcd
for C14H9F3NOS+: 296.0351; found: 296.0355.
15

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2-(2-Chloro-6-(difluoromethoxy)phenyl)benzo[d]thiazole (3n). Yellow oil, 37.4 mg
1
( 60%). H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 7.6 Hz,
1H), 7.55 (t, J = 7.6 Hz, 1H), 7.49-7.41 (m, 3 H), 7.27-7.24 (m, 1H), 6.50 (t, J = 73.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.1, 153.0, 150.3, 136.5, 135.6, 131.6,
1
19
127.1, 126.6, 126.3, 125.7, 123.9, 121.6, 118.7, 115.9 (t, JC-F = 262 Hz). F NMR
(376 MHz, CDCl3) δ -81.54. HRMS (ESI): m/z [M+H]+ calcd for C14H9ClF2NOS+:
312.0056; found: 312.0066.
2-(2-(Difluoromethoxy)naphthalen-1-yl)benzo[d]thiazole (3o). Yellow solid, 45.8
mg (70%), mp 71-73 oC. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.0 Hz, 1H), 8.01
(t, J = 8.4 Hz, 2H), 7.92-7.90 (m, 1H), 7.86 - 7.84 (m, 1H), 7.58 (t, J = 8.0 Hz, 1H),
7.54-7.47 (m, 4H), 6.58 (t, J = 73.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 161.8,
153.3, 146.9, 136.5, 132.9, 132.3, 131.3, 128.1, 128.0, 126.3, 126.2, 125.6, 125.5,
1
19
123.8, 122.4, 121.5, 119.4, 116.4 (t, JC-F = 260 Hz). F NMR (376 MHz, CDCl3) δ
-80.40. HRMS (ESI): m/z [M+H]+ calcd for C18H12F2NOS+: 328.0602; found:
328.0609.
2-(3,5-Dibromo-2-(difluoromethoxy)phenyl)benzo[d]thiazole (3p). Colorless solid,
1
70.5 mg (81%), mp 118-120 oC. H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 2.4 Hz,
1H), 8.13 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.55
(dt, J = 1.2, 7.2 Hz, 1H), 7.46 (dt, J = 0.8, 7.6 Hz, 1H), 6.73 (t, J = 74.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 160.2, 152.4, 144.7, 137.7, 136.2, 132.9, 131.7, 126.6,
1
19
126.1, 123.7, 121.6, 120.6, 118.92, 116.4 (t, JC-F = 260 Hz). F NMR (376 MHz,
CDCl3) δ -82.19. HRMS (ESI): m/z [M+H]+ calcd for C14H8Br2F2NOS+: 433.8656;
16

ACCEPTED MANUSCRIPT
found: 433.8658.
2-(3-Bromo-5-chloro-2-(difluoromethoxy)phenyl)benzo[d]thiazole (3q). Colorless
solid, 51.6 mg (81%), mp 120-121 oC. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 2.4
Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H),
7.55 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 6.73 (t, J = 74.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 160.4, 152.4, 144.2, 136.2, 134.9, 133.2, 131.3, 130.0, 126.6,
1
126.1, 123.8, 121.6, 118.7. 116.5 (t, JC-F = 265 Hz). 19F NMR (376 MHz, CDCl3) δ
-82.18. HRMS (ESI): m/z [M+H]+ calcd for C14H8BrClF2NOS+: 389.9161; found:
389.9162.
2-(2-(Difluoromethoxy)phenyl)-5-methoxybenzo[d]thiazole (3r). Colorless solid,
1
30.7 mg (50%) mp 103-105 oC. H NMR (400 MHz, CDCl3) δ 8.43 (dd, J = 1.6, 7.6
Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.46 (dt, J = 2.0, 8.4 Hz, 1H), 7.38 (d, J = 2.4 Hz,
1H), 7.36 (dt, J = 1.2, 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.11 (dd, J = 2.0, 8.8 Hz,
13
1H), 6.68 (t, J = 73.4 Hz, 1H), 3.90 (s, 3H); C NMR (100 MHz, CDCl3) δ 159.3,
1
157.9, 148.5, 147.1, 137.5, 131.2, 130.2, 125.9, 125.8, 123.8, 119.6, 116.2 (t, JC-F
=
260 Hz), 116.0, 103.5, 55.8; 19F NMR (376 MHz, CDCl3) δ -80.38. HRMS (ESI): m/z
[M+H] + calcd for C15H12F2NO2S+: 308.0551; found: 308.0556.
5-Chloro-2-(2-(difluoromethoxy)phenyl)benzo[d]thiazole (3s). Colorless solid, 52.4
o
1
mg (84%), mp 157-159 C. H NMR (400 MHz, CDCl3) δ 8.48 (dd, J = 1.6, 8.0 Hz,
1H), 8.08 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.51 (dt, J = 1.6, 8.0 Hz, 1H),
7.40 – 7.36 (m, 2H), 7.29 (d, J = 8.0 Hz, 1H), 6.70 (t, J = 73.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 163.6, 153.2, 148.9, 134.3, 132.2, 132.0, 130.5, 125.9, 125.8,
17

ACCEPTED MANUSCRIPT
1
125.1, 123.0, 122.1, 119.3, 116.1 (t, JC-F = 260 Hz).19F NMR (376 MHz, CDCl3) δ
-80.47. HRMS (ESI): m/z [M+H]+ calcd for C14H9ClF2NOS+: 312.0056; found:
312.0067.
5-Chloro-2-(2-(difluoromethoxy)-5-methoxyphenyl)benzo[d]thiazole (3t). Colorless
solid, 41mg (60%), mp 133-135 oC. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 2.0 Hz,
1H), 7.96 (d, J = 3.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 2.0, 8.4 Hz, 1H),
7.22 (d, J = 8.8 Hz, 1H), 7.02 (dd, J = 3.2, 9.2 Hz, 1H), 6.59 (t, J = 73.6 Hz, 1H), 3.91
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.6, 157.3, 153.1, 142.5, 134.4, 132.3,
1
126.3, 125.9, 123.0, 122.2, 121.7, 118.6, 116.4 (t, JC-F = 261 Hz), 113.6, 55.9. 19F
NMR (376 MHz, CDCl3) δ -81.79. HRMS (ESI): m/z [M+H]+ calcd for
C15H12ClF2NO2S +: 342.0162; found: 342.0168.
2-(5-Bromo-2-(difluoromethoxy)phenyl)-5-chlorobenzo[d]thiazole (3u). Yellow
solid, 54.7 mg (70%), mp 160-162 oC. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 2.4
Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.61 (dd, J = 2.4, 8.8 Hz,
1H), 7.40 (dd, J = 2.0, 8.4 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 6.68 (t, J = 72.4 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 161.9, 153.0, 147.6, 134.6, 134.3, 133.0, 132.5, 126.9,
1
126.2, 123.2, 122.2, 121.1, 119.2, 115.8 (t, JC-F = 262 Hz). 19F NMR (376 MHz,
CDCl3) δ -80.82. HRMS (ESI): m/z [M + H] + calcd for C14H8BrClF2NOS +: 389.9161;
found: 389.9159.
5-Chloro-2-(2-(difluoromethoxy)-5-nitrophenyl)benzo[d]thiazole (3v). Yellow solid,
1
36.4 mg (51%), mp 130-132 oC. H NMR (400 MHz, CDCl3) δ 9.44 (d, J = 2.8 Hz,
1H), 8.37 (dd, J = 2.8, 8.8 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H),
18

ACCEPTED MANUSCRIPT
7.47 – 7.43 (m, 2H), 6.84 (t, J = 71.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.8,
152.9, 145.1, 134.4, 132.9, 126.6, 126.4, 126.2, 125.9, 123.5, 122.2, 119.0, 115.3 (t,
19
1JC-F = 265 Hz), 29.70. F NMR (376 MHz, CDCl3) δ -81.79. HRMS (ESI): m/z [M
+ H]+ calcd for C14H8ClF2N2O3S+: 356.9907; found: 356.9911.
General procedure for three-component reaction.
To the sealed tube, 1.0 equivalent (0.2 mmol) of o-hydroxybenzaldehyde 5 and 1.2
equivalents (0.24 mmol) of o-aminothiophenol 4 were added, and 2 mL of EtOH was
further added thereto, and the temperature was slowly raised to 80 oC, and the reaction
was carried out for 12 hours. After completion of the reaction, evaporation of the
solvent under reduced pressure, and then ICF2COOEt 2 (2.0 equiv), KOH (6.0 equiv),
2 mL of acetonitrile were added to the mixture, then stirred at room temperature for
12 hours. After completion of the reaction, evaporation of the solvent under reduced
pressure followed purification by silica gel chromatography using petroleum ether:
ethyl acetate = 50:1 as eluent to give 2-(o-difluoromethoxyaryl) benzothiazole 3.
Evaluation of anticancer activity
The anticancer activity of prepared compounds 3 was determined against human
ovarian cancer cell (SKOV-3). The cell line was cultured in DMEM (TBD)
supplemented with 10% heat inactivated foetal bovine serum (FBS) (PAA
Laboratories) and 1% penicillin/streptomycin (PAA Laboratories). Culture was
o
maintained in a humidified incubator at 37 C in an atmosphere of 5% CO2.
Anticancer activity of prepared compounds 3 and cisplatin at various concentrations
was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
19

ACCEPTED MANUSCRIPT
(MTT) (Sigma) assay, as described by Mosmann, but with minor modification,
following 48 h of incubation. Assay plates were read using a spectrophotometer at 490
nm. Data generated were used to plot a dose–response curve of which the
concentration of test compounds required to kill 50% of cell population (IC50) was
determined. Anticancer activity was expressed as the mean IC50 of three independent
experiments.
Acknowledgements
Financial Supported from National Natural Science Foundation of China (21662017),
and Natural Science Foundation of Jiangxi Province of China (20171BAB205015) is
gratefully acknowledged. We thank Siyun Editing Co., Ltd for linguistic assistance
during the preparation of our manuscript.
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ACCEPTED MANUSCRIPT
1. A new route for the synthesis of 2-(2-(difluoromethoxy)aryl)benzo[d]thiazoles
2. A one-pot, sequential three-component protocol
3. Exhibition promising activity against human ovarian cancer cells